The 1.4 A crystal structure of the class D beta-lactamase OXA-1 complexed with doripenem.

Biochemistry
Kyle D SchneiderRachel A Powers

Abstract

The clinical efficacy of carbapenem antibiotics depends on their resistance to the hydrolytic action of beta-lactamase enzymes. The structure of the class D beta-lactamase OXA-1 as an acyl complex with the carbapenem doripenem was determined to 1.4 A resolution. Unlike most class A and class C carbapenem complexes, the acyl carbonyl oxygen in the OXA-1-doripenem complex is bound in the oxyanion hole. Interestingly, no water molecules were observed in the vicinity of the acyl linkage, providing an explanation for why carbapenems inhibit OXA-1. The side chain amine of K70 remains fully carboxylated in the acyl structure, and the resulting carbamate group forms a hydrogen bond to the alcohol of the 6alpha-hydroxyethyl moiety of doripenem. The carboxylate attached to the beta-lactam ring of doripenem is stabilized by a salt bridge to K212 and a hydrogen bond with T213, in lieu of the interaction with an arginine side chain found in most other beta-lactamase-beta-lactam complexes (e.g., R244 in the class A member TEM-1). This novel set of interactions with the carboxylate results in a major shift of the carbapenem's pyrroline ring compared to the structure of the same ring in meropenem bound to OXA-13. Additionally, bond angles of t...Continue Reading

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Citations

Aug 2, 2013·Accounts of Chemical Research·David A LeonardRachel A Powers
Jun 21, 2012·Journal of the American Chemical Society·Dustin T KingNatalie C J Strynadka
Aug 24, 2011·Antimicrobial Agents and Chemotherapy·Krisztina M Papp-WallaceRobert A Bonomo
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Jan 11, 2011·Journal of Molecular Biology·Kyle D SchneiderDavid A Leonard
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